The role of STAT-6 as a key transcription regulator in HeLa cell death induced by IFN-γ/TNF-α co-immobilized on nanoparticles

The role of STAT-6 as a key transcription regulator in HeLa cell death induced by IFN-γ/TNF-α co-immobilized on nanoparticles

Abstract

Based on the fact that the transcription of STAT-1 plus its Serine 727 and Tyrosine 701 phosphorylation is not the pre-requisite for the cell death signal transduction in the IFN-γ signaling pathway induced by co-immobilized IFN-γ/TNF-α, we investigate both in vitro and in vivo the key transcription regulators to promote the signal transduction of HeLa cells. It is found that IFN-γ R2 is the important death signal receptor in the HeLa cell death by RNA interference. Checking the expression of the whole transcription (STAT) protein family reveals that STAT-6 is highly expressed in comparison with the other STAT proteins. The gene silence of IFN-γ R2 leads to the down-regulation of STAT-6 and phosphorylation-STAT-6 (p-STAT-6) expressions. The successful gene silence of STAT-6 results in the reduction of HeLa cell programmed death and the expression of several important key factors related to programmed cell death (p53, Bcl-2, and Bax). More importantly, our in vivo experiments by injecting nanoparticle drug carriers with the co-immobilized IFN-γ/TNF-α into nude mice model confirm the high expression of STAT-6 and p-STAT-6. It is thus concluded that, in response to IFN-γ, the co-immobilized IFN-γ/TNF-α unusually promotes the activation of STAT-6 rather than STAT-1, resulting in the enhanced cell programmed death in HeLa. The present work reveals the gene-level molecular mechanism of IFN-γ/TNF-α co-immobilized on biomaterials as a potentially effective therapy against cancer cells.